Sensory nerve fibers originate from neurons in the posterior root ganglia and enter the spinal cord through the posterior nerve root. The anterior and posterior nerve roots unite distal to the cord to form a mixed spinal nerve which further combines in the cervical and lumbar areas to form the cervical, brachial, and lumbosacral plexuses. Each plexus gives rise to a number of individual mixed nerves, which are distributed to the periphery to supply muscle, skin, and blood vessels. Small myelinated axons carry sensations for pain and temperature, while so-called unmyelinated axons, which are invested by Schwann cell membranes without sheath formation, carry pain and deeper ill-defined sensation. (Gilroy. 1990. Basic Neurology. Second Edition. (McGraw Hill, Inc.) p. 352).
Under normal conditions, signals (induced, for example, by thermal, mechanical, and chemical stimuli) activate nerve fiber nociceptors and these signals are conducted to the spinal cord. The signals are then transmitted to the thalamus and cerebral cortex resulting in pain awareness (Dray and Urban. 1996. Annu. Rev. Pharmacol. Toxicol. 36:253). Ordinarily, nociceptive pain can be beneficial in that it can serve as a warning mechanism to indicate potential tissue damage. In contrast, chronic pain conditions can develop in which a stimulus and the pain response are not related; i.e., the pain does not serve a physiologically protective purpose.
It has been estimated that 10-20% of the adult population suffer from chronic pain. (Dray and Urban. 1996. Annu. Rev. Pharmacol. Toxicol. 36:253). Chronic pain differs from acute pain in that it can be incessant. Chronic pathologic lesions, neurodgeneration processes, or prolonged dysfunction of parts of the peripheral or central nervous system can cause chronic pain. Chronic pain, for example, can be described as pain which persists beyond the normal healing time for a disease or injury, pain related to chronic degenerative disease or a persistent neurologic condition, pain that emerges or persists (even recurring for months to years without an identifiable cause, or as pain associated with cancer (Markinson. 1996. Am. Journal of Medicine. 101: 1A-6S). Exemplary chronic pain conditions can be grouped into the following exemplary groups: headache or migraine, arthritis (rheumatoid or osteogenic), back pain, musculoskeletal, neurologic or orofacial, cardiac or visceral.
The standard course of treatment for chronic pain involves a step ladder approach which begins with non-opioid analgesics and progresses from moderate opiates to potent opiates. Opiates are often used in combination with other agents. In this way, a physician is able to monitor and adjust the dose of agent to limit the undesired side effects of opioids, which include, e.g., sedation, cognitive impairment, myoclonus, addiction, tolerance, and respiratory depression. However, opiods can induce nausea, constipation, confusion, respiratory depression, and dependence. In addition, opiate tolerance is a well documented side effect observed in chronic pain patients.
Nonsteroidal antiinflammatory drugs (NSAIDs) (which are both antiinflammatory and analgesic) and are also currently used to treat pain. These classes of drugs, however, are also not without side effects. NSAIDs produce gastrointestinal disturbances, ulceration, renal damage, and hypersensitivity reactions. In addition, these drugs must be taken repeatedly to treat chronic pain and can become ineffective with time, resulting in tolerance to the drug.
In addition, current treatments are simply unable to relieve pain in many clinically severe chronic pain disorders, such as, diabetic neuropathy, cervical radiculopathy, neuralgic amyotrophy, HIV neuropathy, neuralgic amyotrophy, fibromyalgia syndrome, or post herpetic neuralgia. Other chronic conditions intractable to current medical strategies are associated with both peripheral and/or central pain such as, post spinal cord injury, muscular dystrophy, trigeminal neuralgia, phantom limb pain, causalgia, and diabetic and alcoholic polyneuropathies. In addition, spasticity of spinal cord origin (e.g., resulting from multiple sclerosis or spinal cord injury) is another condition which often resists current treatments and which can result in chronic pain.
This invention provides methods for alleviating chronic pain and/or spasticity by administering a population of neural cells to thereby treat chronic pain and/or spasticity. Preferably, such treatment results in reestablishing sensory neural pathways in the subject with chronic pain. The present invention is based, at least in part, on the discovery that neural cell populations can be administered into the spinal cord (e.g., to the subarachnoid space or to the spinal dorsal horn) of a subject to treat chronic pain and/or spacticity.
In one aspect, the invention pertains to a method of treating a subject having chronic pain and/or spasticity by administering to the subject a composition comprising a population of isolated, primary neural cells, such that chronic pain and/or spasticity is treated.
In another aspect the invention pertains to a method of treating a subject having chronic pain by administering into the spinal cord of the subject a composition comprising a population of isolated, primary neural cells such that chronic pain is treated.
In another aspect, the invention pertains to a method of treating a subject having chronic pain by administering to the subject a composition comprising a population of isolated, porcine neural cells, such that chronic pain is treated.
In yet another aspect, the invention pertains to a method of treating a subject having chronic pain by administering into the spinal cord of the subject a composition comprising a population of isolated, primary neural cells, such that chronic pain is treated.
In one embodiment, the population comprises fetal porcine neural cells.
In one embodiment, the composition is delivered into the spinal dorsal horn of the subject. In another embodiment, the composition is delivered into the spinal dorsal horn of the subject. In another embodiment, the composition is delivered into the subarachnoid space of the spinal cord.
In one embodiment, the population of neural cells secretes a neurotransmitter. In a preferred embodiment, the neural cell is a gamma-aminobutryic acid (GABA)xe2x80x94releasing neural cell. In another embodiment, the neural cell is a serotonergic cell.
In one embodiment, the population of neural cells comprises human cells. In another embodiment, the population of neural cell comprises fetal human cell.
In one embodiment, the population of neural cells comprises neural stem cells. In a preferred embodiment, the population of neural stem cells is of human or porcine origin.
In one embodiment, the population of neural cells comprises totipotent cells. In a preferred embodiment, the population of neural cells comprises totipotent cells that have been induced to differentiate.
In one embodiment, the population of neural cells comprises neural cells which have been induced to differentiate into a GABA-releasing cell in vitro prior to delivery.
In one embodiment, the population of neural cells comprises neural progenitor cells.
In another embodiment, the population of neural cells comprises neural progenitor cells which have been induced to differentiate into a GABA-releasing cell in vitro prior to delivery.
In one embodiment, the population of neural cells comprises a neural cell which, in unmodified form, has at least one antigen on the cell surface which is capable of stimulating an immune response against the cells in the subject, wherein the antigen on the cell surface is altered such that lysis of the neural cell does not occur upon introduction of the neural cell into the subject and the stimulation of an immune response is inhibited.
In one embodiment, prior to delivery, to the subject the population of neural cells comprises a cell which has been contacted with a non-complement fixing antibody or non-complement fixing fragment of an antibody which binds to at least one antigen on the cell surface which is capable of stimulating an immune response against the cell in the subject to alter the antigen on the cell surface such that an immune response against the cell is inhibited.
In one embodiment, the population of neural cells comprises a cell which has been contacted with at least one anti-MHC class I antibody or fragment thereof, which binds to the MHC class I antigen on the cell surface. In one embodiment, the anti-MHC class I antibody is an anti-MHC class I F(abxe2x80x2)2 fragment.
In one embodiment, the population of neural cells comprises a cell which has been contacted with a F(abxe2x80x2)2 fragment of a W6/32 monoclonal antibody such that an immune response against the cell is inhibited.
In one embodiment, the composition further comprises at least one of the agents or factors selected from the group consisting of neurotrophic factors and anti-inflammatory agents.
In one embodiment, the neurotrophic factor is selected from the group consisting of brain derived neurotrophic factor, ciliary neurotrophic factor, neurotrophin-3, neurotrophin 4/5, nerve growth factor, acidic fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factor, thyrotropin releasing hormone, epidermal growth factor, amphiregulin, transforming growth factor, transforming growth factor xcex2, insulin-like growth factor.
In one embodiment, the anti-inflammatory agent is a steroid. In a preferred embodiment, the steroid is methylprednisolone. In yet another embodiment, the anti-inflammatory agent is selected from the group consisting of cyclosporin A and FK506.
In one embodiment, the neural cell is obtained from a pig which predetermined to be free from at least one organism selected from the group consisting of zoonotic, cross-placental and neurotropic organisms.
In one embodiment, the porcine cell is obtained from the lateral ganglionic eminence of the striatum. In one embodiment, the cell is obtained from the lateral ganglionic eminence of an fetal pig between about days 30 and 40 of gestation.
In one embodiment, prior to delivery to the subject, the cell is contacted with a F(abxe2x80x2)2 fragment of a W6/32 or PT85 monoclonal antibody such that an immune response against the cell is inhibited.
In preferred embodiments, the subject is a human.